Aging is a major factor that contributes to abnormal growth of the prostate leading to the condition of benign prostatic hyperplasia (BPH) in men. Unlike the human prostate, the rodent prostate is organized into different anatomical lobes referred to as the ventral, dorsal and lateral. Each lobe is biochemically distinct and differentially responsive to androgens. Based upon embryologic origin and biochemical function, the lateral and dorsal lobes have been considered homologous to the human prostate, whereas the ventral lobe lacks homology. Past studies in our laboratory have established that spontaneous and androgen-stimulated prostate epithelial cell hyperplasia occurs in the dorsal and lateral, but not the ventral lobe of aging Brown Norway rats. Hence, the age-dependent, lobe-specific prostatic hyperplasia of Brown Norway rats is considered to be a model for human BPH. Our working hypothesis is that aging contributes to a progressive increase in oxidative stress within the prostate, the consequences of which are alterations in the lobe-specific sensitivity to androgen and alterations in cell regulatory mechanisms. These alterations manifest themselves in the form or reactivated cell proliferation and increased cell survival, with the net effect being cellular hyperplasia. The lobe-specific, age-dependent occurrence of hyperplasia provides a unique model to understand the factors that differentially contribute to hyperplasia. In this application, we propose three aims to determine: 1) if changes in androgen sensitivity alter the expression of cell cycle regulatory molecules that activate cell proliferation leading to hyperplasia; 2) if changes in growth factor regulation and expression increase cell proliferation and survival leading to hyperplasia; and 3) if oxidative stress causes damage to lipids, proteins and DNA that correlates with disruption of normal regulation of prostate growth. These studies should lead to a better understanding of the molecular mechanisms that underlie the incidence of prostatic hyperplasia with increasing age, particularly at a time in life when the androgendependent prostate is exposed to a hormonal milieu with paradoxically diminished testosterone concentration.